The present invention relates to medical obstetric procedures and devices and more particularly to the non-invasive monitoring of the human fetus while in the mother""s uterus.
At the present time it is conventional, in medical practice, to ascertain the status and health of a human fetus by ultrasound. Typically a pregnant female may undergo 1 to 4 ultrasound examinations during her pregnancy.
In addition, the heart of the fetus will be detected and monitored using a stethoscope. It is also conventional to monitor the heartbeat of a neonate (newly born infant) during and immediately after childbirth, using a stethoscope or a more sophisticated analysis instrument.
After childbirth, the status of pre-term neonates may be ascertained using EEG (electroencephalography).
An EEG (electroencephalograph) procedure measures neurophysiological activity by measuring the intensity and pattern of electrical signals generated by the brain. Undulations in the recorded electrical signals are called brain waves. The entire record of electrical rhythms and other electrical activity (ongoing background signals and event related transients) of the brain is an EEG. EEGs are widely used to assist in the diagnosis, in children and adults, of epilepsy, brain tumors, physiological disorders and other brain abnormalities. Because the electrical waves produced by an injured or abnormal brain will differ in predictable ways from waves produced by a normal brain, an EEG exam should disclose and help diagnose brain abnormalities and injuries.
Although EEG based brain monitoring of patients has been performed for over 70 years, it is only recently, with the advent of computers and new analysis techniques, that medical professionals have begun to recognize the benefits of EEGs as a broad based diagnostic tool. This should be contrasted with the field of cardiac monitoring in which medical professionals have long been aware of the benefits of monitoring, and have integrated electrocardiogram (xe2x80x9cECGxe2x80x9d) procedures into both preventive and diagnostic health care. As a result, medical device and instrument companies have concentrated on, and provided improved technology for, the fetal cardiac monitoring market. However, EEG technology has not been applied, in general medical usage, to determine the health or status of a fetus.
It has been generally considered that meaningful data could not be gathered non-invasively from the brain of a fetus.
The fetus lies within the uterus surrounded by amniotic fluid. The uterus is within the abdominal cavity of the mother and it is surrounded by layers of skin, muscle and blood. The thickness of the uterine wall and the amount of amniotic fluid vary greatly among different mothers. Consequently, it is difficult to believe that meaningful brain wave signals could be obtained from the fetal brain through all those layers of material. The adult brain produces brain waves in the microvolt range and the fetal brain""s brain waves are weaker than those of a child or adult.
A series of scientific articles have been written about the EEG of neonates. Specifically, tests have been conducted on pre-term at risk neonates (newly born babies) using auditory brain stem auditory evoked response (BAERs). In this BAER procedure a sound (auditory) is transmitted to the neonate. One, or preferably 3 or more, electrodes are placed on the baby""s scalp and the baby""s brain waves are detected as the neuronal responses propagate along the auditory pathways from the auditory nerve to the thalamus. By averaging a series of such responses to the sound, it is possible to identify components of the response which are reproducible, the xe2x80x9cevoked responsesxe2x80x9d of the neonate""s brain are synchronous with the sounds. The xe2x80x9cevoked responsexe2x80x9d is in a time-locked relationship to the auditory stimuli (Taylor 1996; Pasman 1997; Singh 1998; Mercuri 1994; Yasuhara 1986; Cycowisz 1988; Murray 1988; Majnemer 1988; Cox 1992 and Hayakawa). The articles are cited by lead author and date and the patents by patent numbers. They are listed below and are incorporated by reference herein.
Several articles have reported selective vulnerability of auditory nuclei in the pre-term period, especially between 28 and 40 weeks gestational age (GA) (Griffiths, Leech). There have been several reports on the clinical utility of BAERs in newborn infants, particularly with full term infants having asphyxia or hyperbilirubemia or at risk for hearing loss. Neonatal BAER abnormalities have been found in infants with perinatal (at the time of birth) complications (Yashuhara, Cycowisz, Murray). Prognostic value of term BAER assessments has been suggested in studies of later language skills or neurodevelopmental outcome in high risk neonates (Karmel, Majnemer) with low birth weight (Cox) or with neurological signs and demonstrable brain anomalies (Salamy). While all of these reports related to full-term infants, it seems reasonable to propose that the BAER abnormalities existed before delivery and that intrauterine measurements might have provided an early warning of such abnormalities.
In Maynard U.S. Pat. No. 4,308,873 it is suggested that the ongoing EEG of a fetus may be detected by separating the EEG signals from electrocardiograph (ECG) signals. Electrodes are placed directly on the scalp of the fetus during labor (after separation from the uterus).
In accordance with the present invention, the brain waves of the fetus are non-invasively detected and analyzed in a xe2x80x9cFetal Brainstem Monitorxe2x80x9d (FBM). This is a very difficult procedure and requires highly sophisticated techniques and sensitive equipment. However, the evaluation of fetal brain waves may permit the assessment of conditions which may lead to abnormal or delayed intrauterine development and provide a standard for normal fetal development.
It is important, in order to detect such faint fetal brain waves, that they be timed in response to a stimuli. The preferred stimuli are auditory. Preferably a sound generator, for example of click sounds, is placed on the belly of a pregnant woman. The click sounds are transmitted through her skin, muscles, womb and amniotic fluid, to the ears of the fetus. Such transmission of sound is possible because sound travels well through fluids.
One, or more, detecting biosensor electrodes are removably placed on the skin of the mother, proximate her womb. Preferably the electrode is a disposable biosensor which uses an adhesive hydrogel material. It does not require skin preparation or collodion and should provide a low electrical impedance (under 5000 ohms).
The biosensor electrode detects the faint micro-volt level brain waves of the fetus. Because of the faintness of the signals, the amplification which is required is much greater than with conventional EEG amplifiers. In addition, the amplifier should be low in internal noise. Preferably the amplifier connected to the biosensor electrode should have a gain of 200,000 and a noise level of less than 1 microvolt.
The analysis of the EEG is performed using advanced filtering techniques and algorithms relating to Quantitative EEG (xe2x80x9cQEEGxe2x80x9d). These techniques are critical to obtaining meaningful data from the faint electrical brain waves of the fetus. For example, the fetus in the embryonic sac is in almost constant movement, which is considered a muscle artifact and generates noise which may drown out the brain wave signals.
In addition to noise generated by movement of the fetus, the maternal environment produces other noises. These include the heartbeats of the fetus and the mother, movements of the mother (muscle artifacts) such as breathing and eye blinking and the mother""s brain waves, including the mother""s brain wave response to the auditory stimuli.
The following are some of the quantitative approaches to improve the signal-to-noise ratio in this difficult EEG environment.
1. The BAER (Brainstem Auditory Evoked Potentials) are time-locked to the auditory stimuli. The responses are in the interval 1-10 milliseconds (MS) after the stimulus. This time window permits the Fetal Brainstem Monitor (FBM) to receive data only during that period (1-10 MS) following an auditory stimulus. In addition, the elapsed time after each stimulus (latency) of the peak responses of each portion of the brain stem are known, so that data which falls outside of the expected range is discarded. Specifically, the sequence of peaks in the waveshapes of such evoked responses, and the peak amplitudes, reflect activation of the acoustic nerve, cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate, and auditory cortex.
2. Preferably the fetal brain wave signals, after analog-to-digital conversion, will be subjected to xe2x80x9coptimal digital filtering.xe2x80x9d Such filtering removes contaminating noise, in almost real-time (2-5 seconds). This is an adaptation of an optional digital filtering.
3. A procedure involving FFT (Fast Fourier Transform) and IFFT (Inverse Fast Fourier Transform) is used to extract the faint fetal brain waves from the background noise. In a preferred embodiment the procedure uses the following steps:
(a) A xe2x80x9clight averagexe2x80x9d (about 50-500 samples) of data are collected, for example, the BAERs, to 200 auditory stimuli. This is the signal xe2x80x9cSxe2x80x9d.
(b) The same size light averages of data, in the absence of stimuli, is collected for the noise xe2x80x9cNxe2x80x9d.
(c) A number of sets of data representing the signal xe2x80x9cSxe2x80x9d and noise xe2x80x9cNxe2x80x9d are collected, for example, 10 sets of each. In this example, 2000 stimuli would be generated to produce 10 sets of xe2x80x9cSxe2x80x9d data.
(d) A FFT is made of each data set, e.g., 10 of N and 10 of S.
(e) For each resulting pair of FFT (each xe2x80x9cbinxe2x80x9d of FFT is one data set of N and one of S), the F-ratio is computed. The F-ratio, in this case, is the Phase Variance S/Phase Variance N.
(f) A threshold has been set, based on prior experience, for an acceptable F-ratio, i.e., a significant value of F-ratio.
(g) The phase variance F-ratios are scanned for all frequencies of FFT from 0 to 5 KHz.
(h) For those frequencies where the F-ratio is not significant, set the coefficients to zero.
(i) perform an IFFT on the remaining terms (the non-zero terms.
(j) average the IFFT, which provides relatively noise-free signals.
Preferably the entire procedure (a)-(j) is repeated (iteration), for example, three times, to provide the final result. In terms of time, the 2000 stimuli and equal non-stimuli time, may take less than 3 minutes and the entire test (3 iterations) would take less than 9 minutes.
4. xe2x80x9cNeurometricxe2x80x9d analysis is applied to determine if data is within the bounds of expected signals defined by normative data and the statistical significance of each peak in the fetal brain wave data. Neurometric analysis is a statistically based set of techniques and algorithms which collects data from normal groups of developing fetuses. The fetus being monitored at each state of fetal development is compared to the xe2x80x9cnormalxe2x80x9d group to ascertain if the BAERs are normal or abnormal and, if abnormal, the locus, extent and nature of the abnormality. In another embodiment, the state of the fetal brain is assessed relative to an initial state in the fetus and the fetus serves as its own xe2x80x9cnorm.xe2x80x9d Such self-norming allows comparison of successive measurement relative to some prior state.